Partition coefficients peptides

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

In this model, one can argue that a peptide must have both an affinity for the interface (favorable n-octanol partition coefficient) and small desolvation energy (favorable A log PC) in order to efficiently cross a cell membrane. On the other hand, this model also predicts that a peptide with a large n-octanol/water partition coefficient and large desolvation energy, due to a significant number of polar groups, should adsorb and remain at the membrane interface. Both of these predicted events have been observed in the laboratory. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Fig. 37), suggesting that desolvation of the polar bonds in the molecule is a major determinant of permeability. Consistent with this, good correlations were found between the permeabilities of these peptides and their partition coefficients between heptane-ethylene glycol (r2 = 0.87) or the differences in partition coefficients between n-octanol-buffer and isooctane-buffer (r2 = 0.82) both these buffer systems provide experimental estimates of hydrogen-bonding potential. These results are qualitatively identical with those described earlier for the permeability of these peptides across Caco-2 cell monolayers. 

A careful comparative pharmacokinetic study of the tripeptoid 6.108 and the tetrapeptide N-phenylacetyl-Leu-Asp-Phe-D-Pro-amide (6.109) in rats has provided insights on absorption and disposition [233]. The two compounds have comparable backbone structures but differ in the presence or absence of peptide bonds. They also have similar octanol/water partition coefficients, although the H-bonding capacity of the tetrapeptide is greater. In an in vitro model, the two compounds had comparable, and low, absorption clearances (6.7 x 10 4 vs. 4.8 x 10 4 ml min-1 cnT1 for the peptoid and the... 

The peptide (melittin) was foimd associated to RMs in a single state as opposed to involvement of at least two forms of melittin with Upid in phospholipid vesicles. Folding and dynamics of this peptide in RMs were also investigated In RMs, activity of a-chymotrypsin was imaffected by pressurization while lipase lost its activity at low pressures and regained on depressurization. The use of pressure as a switch for lipase catalysis is discussed Partition coefficients for 11 amino acids, 17 dipeptides and 5 longer peptides in RMs were determined. 

Tab. 4.5 Caco-2 cell permeability and octanol-buffer partition coefficients (P) forthe studied peptides (seeTab. 4.4). (Adapted from Tab. 2 of ref. 36)...

Cell viability studies of HT29 colon cancer cells treated with the CO-releasing compound [Mn(CO)3(tpm)]PF6, 33 R = H, revealed a significant photoinduced cytotoxicity comparable to that of established agent 5-fluorouracil [205]. Subsequently, [Mn(CO)3(tpm)]PF6, 33, was modified by replacing R with peptides to permit cellular recognition [206]. 34, R = H, Me, releases nearly 2 mol of CO to myoglobin on photolysis while 35, E = lone pair, O, S, releases approximately 1 mol of CO. The n-octanol/water partition coefficients were also measured [207]. 

Oligomers of glycine show little appreciable retention on octyl silica with 20 mM phosphate buffers over the pH range 2.10-7.83 (46), or on octadecyl silica with 100 mM phosphate buffer, pH 2.1 (33), or 5 mM phosphate buffers, pH 2.1, containing hydrophobic alkyl sulfonates (30). It is thus likely that the peptide chain proper makes only a very small contribution to the retention of peptides under these conditions. Based on partition coefficient considerations, oligomers of alanine, and the other nonpolar amino acids, should show a linear dependence of log A on the number of residues. This, in fact, has been observed. For example, the plot of log A versus the number of alanine residues shows (33) a linear dependence with a uniform log A increment due to the methyl group of the aliphatic side chain (Fig. 2), i.e., the effect is additive (45a, 46a). 

It is widely accepted that the two most important physicochemical parameters that determine a molecule s skin permeability are a) its lipophilicity, with a log (octanol/water partition coefficient) value of 2 being quite favorable, and b) its molecular size— smaller compounds permeating better than big ones. " Thus, it is no surprise that the passive transdermal delivery of peptides and proteins, which are typically either very polar (or charged) and/or of high molecular weight (>1000 Da), is extremely inefficient and rarely results in fluxes, which would elicit significant therapeutic effect. 

Stoichiometric ratios of anionic detergents, such as sodium dodecyl sulfate (SDS), have been used to complex peptides and increase their partition coefficient into non-polar solvents by two- to four-fold (Powers et al., 1993). For example, insulin was complexed with SDS and resulted in a ten-fold increase in solubility in 1-octanol. The insulin remained in its native conformation with... 

Kakisaka, K. et al.. Partition coefficients of amino acids, peptides, and enzymes in Dextran/PEG/water aqueous two phase systems, J. Chem. Eng. Jpn., 31, 991, 1998. 

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